2-Substituted thiazole-4-carboxamide derivatives as tiazofurin mimics: synthesis and in vitro antitumour activity

Tiazofurin analogues bearing a 5-hydroxymethyl-2-methyl-tetrahydrofuro[2,3-d][1,3]dioxol-6-ol moiety as a sugar mimic (2 and 3), and two novel thiazole-based acyclo-C-nucleosides 4 and 16 have been synthesized in multistep sequences starting from d-xylose (compounds 2 and 3) or from d-arabinose (compounds 4 and 16). All synthesized analogues showed potent in vitro antitumour activities against a panel of human tumour cell lines. Flow cytometry data suggest that cytotoxic effects of analogues 2–4 and 16 in the culture of K562 cells might be mediated by apoptosis. It was also found that these analogues induced changes in cell cycle distribution of K562 cells. Results of western blot analysis (upregulation of Bax and downregulation of Bcl-2, activation of caspase-3 and the presence of a PARP cleavage product) suggest that tiazofurin mimics (2–4 and 16) in K562 cells induced apoptosis in a caspase-dependent way.     

Surface Roughness Characterization of Poly(methylmethacrylate) Films with Immobilized Eu(III) β-Diketonates by Fractal Analysis

The structural complexity of the 3-D surface of poly(methylmethacrylate) films with immobilized europium β-diketonates was studied by atomic force microscopy and fractal analysis. Fractal analysis of surface roughness revealed that the 3-D surface has fractal geometry at the nanometer scale. Poly(methylmethacrylate) (PMMA) as immobilization matrix is dense and uniform, and a tendency for formation of chain structures was observed. Fractal analysis can quantify key elements of 3-D surface roughness such as the fractal dimensions D _f determined by the morphological envelopes method of the Eu(DBM)₃ and Eu(DBM)₃ · dpp nanostructures, which are not taken into account by traditional surface statistical parameters.     

Investigation on the catalytic activity of doped low-percentage oxide catalysts Mn/ZnO obtained from oxalate precursor

The precursors with a low manganese content ≤ 0.07% Mn were synthesized by spontaneous crystallization from Zn²⁺, Mn²⁺ and C₂O₄ ²⁻-containing solutions. The initial ratio Zn²⁺:C₂O₄ ²⁻ = 1:1 and 1:2 influences the morphology and prevailing orientations of the crystallites in the oxalate samples. The presence of such small Mn content in the samples does not change the morphology or size of the crystals. The ZnO and Mn/ZnO oxides with manganese content from 0.51×10⁻² to 15.1×10⁻² Wt % are obtained after thermal decomposition of the oxalates. The oxides preserved the morphology of the precursors. The catalytic tests show that the pure ZnO has a poor activity for CO oxidation reaction. Its doping with Mn promotes the catalytic activity (up from twice to five times) in spite of the very low contents of the dopants. The observed increase of the activity depends on both dopant concentration and Zn²⁺:C₂O₄ ²⁻ ratio, probably due to the different mechanism of the manganese inclusion and different morphology of the oxides. The catalysts of the 1:2 series are more active in CO oxidation reaction.      

Asymptotics of zeros of polynomials arising from rational integrals

We prove that the zeros of the polynomials Pm(a) of degree m, defined by Boros and Moll via

     

Gaussian extended cubature formulae for polyharmonic functions

The purpose of this paper is to show certain links between univariate interpolation by algebraic polynomials and the representation of polyharmonic functions. This allows us to construct cubature formulae for multivariate functions having highest order of precision with respect to the class of polyharmonic functions. We obtain a Gauss type cubature formula that uses values of linear functionals (integrals over hyperspheres) and is exact for all -harmonic functions, and consequently, for all algebraic polynomials of variables of degree .

     

Sharp bounds for the extreme zeros of classical orthogonal polynomials

Bounds for the extreme zeros of the classical orthogonal polynomials are obtained by a surprisingly simple method. Nevertheless, it turns out that, in most cases, the estimates obtained in this note are better than the best limits known in the literature.     

Influence of Data Acquisition Environment on Accuracy of Acoustic Voice Quality Measurements

Accuracy of acoustic voice analysis is influenced by the quality of recording. Lately, articles have suggested that soundcards perform equivalently to specialized professional-grade data acquisition (DA) systems. The purpose of this study was to investigate the influence of DA environment (DA system and microphone) on acoustic voice quality measurement (VQM) while balancing for gender, age, intersubject and intrasubject variability, and analysis software. More specifically, the relative performance of different hardware environments and the relationship between their technical characteristics and VQM performance was investigated. The discretization error and the effective dynamic range of the different DA environments were measured. We used 3 software systems to record and measure separately 2000 acoustic samples of sustained phonation for fundamental frequency, jitter, and shimmer. Analyses of variance (ANOVA) were performed with these parameters as the dependent variables. The results of the study suggested that professional-grade DA hardware is strongly recommended to provide accurate and valid voice assessment. The fundamental frequency measurement differences across DA environments were highly correlated to the discretization error (r=1.00), whereas jitter and shimmer were highly correlated to the effective dynamic range of the DA environments (r=-0.68 and r=-0.86, respectively).     

Zero sets of bivariate Hermite polynomials

We establish various properties for the zero sets of three families of bivariate Hermite polynomials. Special emphasis is given to those bivariate orthogonal polynomials introduced by Hermite by means of a Rodrigues type formula related to a general positive definite quadratic form. For this family we prove that the zero set of the polynomial of total degree n+m$n+m$ consists of exactly n+m$n+m$ disjoint branches and possesses n+m$n+m$ asymptotes. A natural extension of the notion of interlacing is introduced and it is proved that the zero sets of the family under discussion obey this property. The results show that the properties of the zero sets, considered as affine algebraic curves in R²${\mathbb{R}}^2$, are completely different for the three families analyzed.     

Antitumour tiazofurin analogues embedded with an amide moiety at the C-2′ position

Synthesis of four new tiazofurin analogues has been accomplished starting from d-glucose. The key step of the synthesis was the three-step cascade that enabled an efficient hydrogen sulfide mediated one-pot conversion of 2-azido-3-O-acyl-ribofuranosyl cyanides to the corresponding 2-alkylamido ribofuranosyl thiocarboxamides. The resulting key intermediates were first converted to protected tiazofurin derivatives by cyclocondensation with ethyl bromopyruvate, and finally to target C-nucleosides by treatment with ammonia in methanol. In vitro cytotoxicities of tiazofurin analogues against a number of human tumour cell lines were recorded and compared with those observed for the parent molecule (tiazofurin), as well as the commercial antitumour agent doxorubicin (DOX). Analogues 2b-d have shown a potent in vitro cytotoxic activity against human myelogenous leukaemia K562. Among solid tumour cell lines, HT29 was sensitive only to 2d, while HeLa cells were sensitive to 2a, 2b and 2d. Only analogue 2a was highly cytotoxic against MCF-7 cells. No tiazofurin analogue exhibits any significant cytotoxicity towards normal foetal lung MRC-5 cells. Downregulation of Bcl-2, activation of caspase-3 and presence of cleavage product of PARP suggest that the cytotoxic effects of tiazofurin analogues 2a-d in K562 might be mediated by apoptosis in a caspase-dependent way. On the contrary, tiazofurin did not induce apoptosis of K562 cells, which suggests a different mechanism of action, most probably through the inhibition of IMPDH. Flow cytometry and Western blot analysis data agreed well with the results of MTT assay, and enabled identification of analogue 2c as the most promising antitumour agent that preferentially target cancer cells over normal cells and thus represents a new lead for further optimization.